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The Journals of Gerontology Series A: Biological Sciences and Medical Sciences 62:932-942 (2007)
© 2007 The Gerontological Society of America

Reduction in Glutathione Peroxidase 4 Increases Life Span Through Increased Sensitivity to Apoptosis

Qitao Ran1,3, Hanyu Liang, Yuji Ikeno1,3, Wenbo Qi, Tomas A. Prolla, L. Jackson Roberts, II5, Norman Wolf, Holly VanRemmen1,3 and Arlan Richardson1,3,

1 Department of Cellular and Structural Biology, and 2 Barshop Institute for Longevity and Aging Studies, the University of Texas Health Science Center at San Antonio.
3 Geriatric Research, Education and Clinical Center, South Texas Veterans Health Care System, San Antonio.
4 Departments of Genetics & Medical Genetics, University of Wisconsin-Madison.
5 Departments of Pharmacology and Medicine, Vanderbilt University, Nashville, Tennessee.
6 Department of Pathology, University of Washington, Seattle.

Address correspondence to Arlan Richardson, PhD, Barshop Institute for Longevity and Aging Studies, 15355 Lambda Drive, San Antonio, TX 78245-3207. E-mail: richardsona{at}uthscsa.edu

Glutathione peroxidase 4 (Gpx4) is an antioxidant defense enzyme that plays an important role in detoxification of oxidative damage to membrane lipids. Because oxidative stress is proposed to play a causal role in aging, we compared the life spans of Gpx4 heterozygous knockout mice (Gpx4+/– mice) and wild-type mice (WT mice). To our surprise, the median life span of Gpx4+/– mice (1029 days) was significantly longer than that of WT mice (963 days) even though the expression of Gpx4 was reduced approximately 50% in all tissues of Gpx4+/– mice. Pathological analysis revealed that Gpx4+/– mice showed a delayed occurrence of fatal tumor lymphoma and a reduced severity of glomerulonephritis. Compared to WT mice, Gpx4+/– mice showed significantly increased sensitivity to oxidative stress-induced apoptosis. Our data indicate that lifelong reduction in Gpx4 increased life span and reduced/retarded age-related pathology most likely through alterations in sensitivity of tissues to apoptosis.






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